NDLI: Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability

Content Provider	Springer Nature : BioMed Central
Author	Jin, Han Zhang, Cheng Nagenborg, Jan Juhasz, Peter Ruder, Adele V. Sikkink, Cornelis J. J. M. Mees, Barend M. E. Waring, Olivia Sluimer, Judith C. Neumann, Dietbert Goossens, Pieter Donners, Marjo M. P. C. Mardinoglu, Adil Biessen, Erik A. L.
Abstract	Background Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking. Methods In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque. Results Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH−) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment. Conclusions This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.
Related Links	https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-024-02339-3.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
ISSN	14752840
DOI	10.1186/s12933-024-02339-3
Journal	Cardiovascular Diabetology
Issue Number	1
Volume Number	23
Language	English
Publisher	BioMed Central
Publisher Date	2024-07-08
Access Restriction	Open
Subject Keyword	Diabetes Angiology Cardiology Plaque rupture Macrophage Genome-scale metabolic network Atherosclerosis Metabolomics
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine Internal Medicine Endocrinology, Diabetes and Metabolism
Journal Impact Factor	8.5/2023
5-Year Journal Impact Factor	8.9/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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